Abstract Despite the advent of biological therapies, glucocorticoids (GCs) remain the most widely prescribed medicines for the management of inflammatory diseases such as lupus, asthma, multiple sclerosis, and rheumatoid arthritis. However, long term and high dose GC use is inevitably accompanied by systemic toxicity. There are no adjunctive therapies that could enhance the disease modifying effects of GCs at low doses thus minimizing their dose-dependent toxicity. The long-term product goal of this Phase I SBIR project is a small molecule GC adjunct that will enable an efficacious GC regimen at non-toxic doses. To accomplish this goal, we propose an innovative strategy to improve GC responsiveness by blocking macrophage migration inhibitory factor (MIF), a proinflammatory cytokine known for its ability to antagonize GC action. We will block MIF function using a novel family of small molecule MIF inhibitors and a MIF-specific monoclonal antibody and evaluate the therapeutic effect of this blockade in restoring GC response in a GC-resistant autoimmune disease model. For the purpose of this study, we have already developed a unique mouse model of autoimmune disease that is refractory to GC treatment. In this model of experimental autoimmune encephalomyelitis (EAE), the rodent equivalent of multiple sclerosis, we discovered that female mice develop fulminant and lethal disease despite GC treatment, and that disease progression can be effectively halted by neutralizing MIF activity. Building from this observation, we have developed a rigorous experimental plan to interrogate the therapeutic effect of MIF inhibition in restoring GC responsiveness in the EAE mice. The achievable milestone for this Phase I SBIR project is efficacy evaluation of two novel small molecule MIF inhibitors and one MIF-specific monoclonal antibody in restoring GC response in the GC-resistant EAE mice. The scientific premise of this study is based on a vast body of literature on the interactions between MIF and GCs, and the relevance of this regulatory dyad in contributing to clinical resistance to GC therapy. A successful outcome of this study will lay the foundation for further pre-clinical development of a novel and `first-in-class' adjunctive therapy that would enable prolonged use of lower and non-toxic doses of GCs in autoimmune patients.